Neuropilin-1 is a T cell memory checkpoint limiting long-term anti-tumor immunity

Robust CD8(+) T cell memory is essential for long-term protective immunity, but is often compromised in cancer where T cell exhaustion leads to loss of memory precursors. Immunotherapy via checkpoint blockade may not effectively reverse this defect, potentially underlying disease relapse. Here we report that mice with a CD8(+) T cell-restricted neuropilin-1 (NRP1) deletion exhibited substantially enhanced protection from tumor re-challenge and sensitivity to anti-PD1 immunotherapy, despite unchanged primary tumor growth. Mechanistically, NRP1 cell-intrinsically limited the self-renewal of the CD44(+)PD1(+)TCF1(+)TIM3(–) progenitor exhausted T cells (pT(EX)), which was associated with their reduced ability to induce c-Jun/AP-1 expression upon T cell receptor (TCR) re-stimulation, a mechanism that may contribute to terminal T cell exhaustion at the cost of memory differentiation in wildtype tumor-bearing hosts. These data suggest that blockade of NRP1, a unique “immune memory checkpoint”, may promote the development of long-lived tumor-specific T(MEM) that are essential for durable anti-tumor immunity.